DEMYELINATION IN MULTIPLE SCLEROSIS

我们研究的长期目标是了解生物化学和 发生在免疫介导的脱髓鞘的分子过程 多发性硬化症和格林-巴利综合征等疾病。我们有 以前我们的研究主要集中在脱髓鞘的病理生物学上。 通过补体，尤指膜反应性末端补体 络合物(TCC)。前一批资助期内的实验结果 我们发现髓鞘通过直接的C1激活补体 结合，并允许TCC形成，这是脱髓鞘所必需的 髓鞘培养。移行细胞癌可能导致髓鞘板层分裂和 髓鞘囊泡形成，因为结构性髓鞘有效水解性 TCC可以通过激活髓鞘来诱导MBP等蛋白质的表达 蛋白酶。在少突胶质细胞(OLG)中，TCC动员花生四烯酸 (Aa)和LTB4。此外，亚溶质TCC被发现选择性地减少 编码蛋白脂和MBP(但不编码β-肌动蛋白)的mRNA积累。 在转录抑制物存在的情况下也可以看到这种TCC效应， 表明信使核糖核酸加速衰退。因此，髓鞘的形成是一种重要的 OLG的功能，会受到补体的影响。 在本应用中，我们将通过以下方式研究AA动员的机制 探索激活脂肪酶所需的信号信使 AA由TCC生产。髓鞘吞噬的效率通过 补体衍生调理肽、补体C3b和补体C3b介导的巨噬细胞 IC3b，将进行评估。我们发现髓鞘中没有DAF膜 下调补体级联的蛋白质。因此，增加了 C3b和iC3b对髓鞘的调理作用将增强巨噬细胞介导的 与补体相互作用对髓鞘的损伤和清除 受体CR1和CR3表达于巨噬细胞。此外，分子 髓鞘蛋白的转录后调控机制 将对TCC的基因进行调查。核糖核酸序列特异性基序(S) 这是导致mRNA加速衰退的原因，作为对 TCC诱导的信号将被识别。最后，美国政府的作用 免疫介导的脱髓鞘中的补体系统将在 活着。具体地说，髓鞘直接激活C1在体内的作用 随后将检查血脑屏障的破坏情况以及 TCC在炎性脱髓鞘中的作用。

The long term goal of our research is to understand the biochemical and molecular process underlying immune mediated demyelination occurring in diseases such as multiple sclerosis and Guillain Barre syndrome. We have previously focused our studies on pathobiology of demyelination induced by complement, especially the membrane-reactive terminal complement complexes (TCC). Experimental results during the preceding grant period are summarised; We found that myelin activates complement by direct C1 binding, and allows TCC to form, which is required for demyelination of myelinating cultures. The TCC may cause splitting myelin lamellae and myelin vesiculation, since effective hydrolysis of structural myelin proteins such as MBP can be induced by TCC through activation of myelin proteases. In oligodendrocytes (OLG), TCC mobilizes arachidonic acid (AA) and LTB4. In addition, sublytic TCC was found to selectively reduce the MRNA accumulation encoding proteolipid and MBP (but not beta-actin). This TCC effect was also seen in the presence of transcription inhibitor, indicating accelerated MRNA decay. Thus, myelin formation, an important function of OLG, can be affected by complement. In this application, we will study the mechanisms of AA mobilization by exploring signal messengers required to activate lipases responsible for AA production by TCC. The efficiency of myelin phagocytosis by macrophages mediated by complement-derived opsonic peptides, C3b and iC3b, will be evaluated. We found that myelin is devoid of DAF, membrane protein which down-regulates complement cascade. Therefore, increased opsonization of myelin by C3b and iC3b will enhance macrophage-mediated damage and clearance of myelin through interaction with complement receptors, CR1 and CR3, expressed on macrophages. In addition, molecular mechanisms involving post-transcriptional regulation of myelin protein genes by TCC will be investigated. The RNA Sequence-specific motif(s) which is responsible for the accelerated MRNA decay, in responds to the signal induced by TCC, will be identified. Finally, the role of the complement system in immune-mediated demyelination will be examined in vivo. Specifically, the role of C1 activation directly by myelin in vivo following breakdown of blood brain barrier will be examined as well as the role of TCC in inflammatory demyelination.